16th International HIV Drug Resistance Workshop 12-16 June 2007, Barbados

SYNERGY OF A HEPATITIS C VIRUS (HCV) NS4A ANTAGONIST, ACH-806, IN COMBINATION WITH HCV PROTEASE OR POLYMERASE INHIBITORS

Antivir Ther. 2007; 12:S29 (abstract no. 27)

DL Wyles, KA Kaihara and RT Schooley
University of California, San Diego, La Jolla, CA, USA

BACKGROUND AND AIMS: The majority of compounds evaluated in vitro and in early clinical trials belong to one of three classes of HCV inhibitors: NS3 protease inhibitors (PI), NS5B nucleoside inhibitors, and NS5B non-nucleoside inhibitors. Resistance to each of these compound classes has been described with some mutations conveying crossresistance (e.g. A156T in HCV protease). ACH-806 is a novel acylthiourea inhibitor of HCV replication with a unique mechanism of action. A Phase I study demonstrated significant in vivo activity for ACH-806. Protease inhibitor resistant replicons are fully sensitive to ACH-806; conversely, ACH-806 resistant replicons remain susceptible to protease and polymerase inhibitors. We sought to evaluate ACH-806 in combination with other small molecular inhibitors of HCV replication.

METHODS: Compounds were evaluated singly and in combination in 96-well plates using cells stably expressing a HCV genotype 1b luciferase reporter replicon. Fixed ratio combinations consisted of two twofold serial dilutions above and below the IC₅₀ of the individual compounds. Compounds were incubated for 48 h and luminescence assayed (Bright-glo, Promega). Compounds tested: ACH- 806; peptidomimetic HCV PIs- BILN 2061 and Vertex PI; a trans-lactam GSK PI; HCV RNA dependent RNA polymerase inhibitors- one nucleoside (2′-C-methyladenosine), one GSK thiadiazine non-nucleoside inhibitor (NNI); and interferon-a. Combination indices (CI) were determined using Calcusyn (Biosoft). A CI of <0.9 was considered synergistic, ≥0.9 and ≤1.1 additive, >1.1 antagonistic.

RESULTS: IC₅₀ (±SEM) for the individual compounds: ACH-806 116.8 nM (±5.4), IFN-α 4.5 IU/ml (±0.6), Vertex PI 310.3 nM (±48.4), BILN-2061 9.3 nM (±0.7), GSK-PI 301 nM (±23.9), 2′-C-methyladenosine 446.8 nM (±46.2), and GSK-NNI 3.5 µM (±0.4). Combinations indices at the IC₇₀ level (CI70 ±SEM) were: IFN 0.93 ±0.12, Vertex PI 0.79 ±0.03, BILN-2061 0.81 ±0.08 , GSK-PI 0.68 ±0.06, methyladenosine 0.72 ±0.07 and GSK-NNI 0.73 ±0.10.

CONCLUSIONS: The HCV NS4A antagonist, ACH- 806 is synergistic with small molecular inhibitors of HCV replication representative of the compound classes currently being tested in clinical trials. Inhibitors which posses complementary actions in vitro (synergy) and have divergent resistance pathways should be prioritized for study in clinical trials of combination therapy for HCV. ACH-806 and other compounds with a similar mechanism of action represent attractive compounds to potentially combine with both protease and polymerase inhibitors.

Acknowledgements: This work was funded in part by a 2005 developmental grant from the UC San Diego Center for AIDS Research, an NIH funded program #5P30 AI-36214.

2007-06-12
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